Aripiprazole in the real-world treatment for irritability associated with autism spectrum disorder in children and adolescents in Japan: 52-week post-marketing surveillance

Background The purpose of this study was to evaluate the post-marketing safety and effectiveness of aripiprazole in treating irritability in pediatric patients (6–17 years) with autism spectrum disorder (ASD) in actual clinical sites of Japan. Methods In this post-marketing surveillance, patients were enrolled into the multicenter, prospective, non-interventional, observational study for 52 weeks, and were dosed with aripiprazole (1–15 mg/day) under daily clinical settings in Japan. Results In 510 patients, the continuation rate of aripiprazole treatment was 84.6% at day 168 (week 24) and 78.1% at day 364 (week 52). Adverse drug reactions (ADRs) occurred in 22.7% of patients (n = 116), and the most common ADRs were somnolence (9.4%), followed by weight increased (3.3%). At week 4, the mean change from baseline in the irritability subscale score for the Aberrant Behavior Checklist Japanese version (ABC-J) was − 5.7 ± 6.8 (n = 288). Based on multiple regression analysis, comorbid attention deficit and hyperactivity did not affect the ABC-J irritability subscale score at endpoint. At week 24, the mean change from baseline for the Strengths and Difficulties Questionnaire was − 3.3 ± 4.9 (n = 215) for the total difficulties score and 0.6 ± 1.7 (n = 217) for the prosocial behavior subscale score. Conclusions Aripiprazole was well tolerated and effective in the long-term treatment of irritability associated with ASD in Japanese pediatric patients in the real-world clinical practice. Trial registration This surveillance was registered with Clinical Trial.gov (no. NCT03179787) on June 7, 2017 (retrospectively registered). Supplementary Information The online version contains supplementary material available at 10.1186/s12888-021-03201-6.


Background
Autism spectrum disorder (ASD) is characterized by persistent impairment in reciprocal social communication and social interaction, and restricted, repetitive patterns of behavior, interests, or activities. These symptoms are present from early childhood and limit or impair everyday functioning. The impairments in communication and social interaction are pervasive and sustained [1]. Understandably, these symptoms can have a substantial impact on the individuals and their families. This impact can be further increased by the presence of associated behaviors such as irritability, which may manifest as tantrums, aggressiveness, self-injurious behaviors, and sudden mood changes, all of which can have a significant impact on education and social development [2].
Although there are no approved pharmacologic treatments that target core deficits of ASD, associated secondary symptoms such as irritability may be ameliorated by a combination of behavioral and pharmacologic approaches, including the use of atypical antipsychotics [3].
Aripiprazole is an atypical antipsychotic drug developed by Otsuka Pharmaceutical Co., Ltd. that is characterized by partial agonism at dopamine D 2 receptors and serotonin 5-HT 1A receptors and antagonism at 5-HT 2A receptors [4,5]. In the pediatric field, the indications for adolescent schizophrenia (13 to 17 years), pediatric bipolar mania (10 to 17 years), irritability associated with autistic disorder (6 to 17 years), and Tourette's disorder (6 to 18 years) in the United States, and schizophrenia in adolescents aged 15 years and older in Europe have been approved [6,7]. Aripiprazole may have a more favorable side-effect profile than other antipsychotics in child and adolescent patients with mental health disorder [8] because of its unique mechanism of action.
The indication for irritability associated with autistic disorder (6 to 17 years) with oral aripiprazole has been approved in the United States since 2009 and in 5 countries thereafter, and the efficacy was also confirmed in clinical trials in children and adolescents with irritability associated with ASD in Japan [9][10][11]. Based on the trials, the indication for irritability associated with ASD in children and adolescents has been approved since September 2016 in Japan.
The clinical studies that started before 2013 included the patients diagnosed with autistic disorder based on the diagnostic criteria of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) [12]. Before starting this surveillance, DSM-IV-TR had been updated to DSM-5 [1], and the indication was changed to ASD. Since diagnosis with comorbid ASD and attention deficit and hyperactivity disorder (ADHD) was recognized, the scope of applicable patients in this surveillance has been broader than in the clinical study. Also, the criteria for patient selection and concomitant medications are strictly specified in randomized controlled clinical trials and do not necessarily reflect the actual clinical treatment environment. Therefore, this post-marketing surveillance was conducted to assess the real-world safety and effectiveness of aripiprazole for children and adolescents with ASD-related irritability in Japan.

Patients
Patients newly treated with aripiprazole for irritability associated with ASD in children and adolescents (≥6 years and < 18 years) were included in the surveillance. The target sample size was calculated to be 300 patients on the assumption of detecting adverse drug reactions (ADRs) occurring at a frequency of 1% with a confidence of at least 95%.

Study design
This surveillance was conducted as a multicenter, prospective, non-interventional, observational study for 52 weeks (1 year). The registry and case reports were encoded by the physicians through Electronic Data Capture system during the period from April 2017 to September 2019.
This surveillance was conducted in compliance with the Ministerial Ordinance on Standards for Conducting Post-marketing Surveys and Studies on Drugs; MHLW Ordinance No. 171 issued on December 20, 2004 (GPSP). As the surveillance is a non-interventional study in accordance with GPSP, the need for ethics approval and consent were waived. The surveillance was designed by Otsuka, reviewed by the Japanese Pharmaceutical and Medical Devices Agency (PMDA), and also registered at Clinical Trials.gov (identifier: NCT03179787).
Aripiprazole was administered orally once daily with a starting dose of 1 mg daily and a maintenance dose of 1-15 mg daily according to the package insert in Japan [17]. The dose could be adjusted according to the severity of patient's symptoms, however the dose increase per day was to be 3 mg or less and the daily dose was not to exceed 15 mg [17].

Patient demographics
Patients' gender, age, body height, weight, severity of symptoms, duration of illness, comorbidities, medical history, concomitant medications, etc. were recorded before aripiprazole administration.

Aripiprazole dosing
The daily dose of aripiprazole, administration period (start date and end date), and reasons for discontinuation (if discontinued) were recorded.

Safety
The adverse events (if any occurred), onset date, seriousness, outcome, date of outcome, causality to aripiprazole, other possible causal factors, and treatment for adverse events during the observation period were recorded. Seriousness was determined by the physicians.
Body weight and height were also recorded. The shift in the percentile body weight category from baseline to end-point was calculated using predefined body weight percentile categories.

Effectiveness
Using caregiver-rated Aberrant Behavior Checklist-Japanese version (ABC-J), the degree of aberrant behaviors was scored on four levels ranging from 0 'not at all a problem' to 3 'the problem is severe in degree', totaling 58 items. These items were classified into five subscales: irritability (15 items), lethargy/social withdrawal (16 items), stereotypy (7 items), hyperactivity (16 items), and inappropriate speech (4 items), and scores were calculated [18].
Physician-rated Clinical Global Impression-Improvement (CGI-I) and Severity of illness (CGI-S) scales quantified the physician's impression at baseline (CGI-S only), week 4, week 8, week 16, week 24, and week 52, or at the time of discontinuation of aripiprazole administration. The CGI-I scale was scored from 1 'very much improved' to 7 'very much worse', and CGI-S was scored from 1 'normal' to 7 'very much severely ill'.
Caregiver-rated Strengths and Difficulties Questionnaire for Children (SDQ) was used to score the adaptation and mental health conditions on three levels: 0 'not true', 1 'somewhat true', and 2 'certainly true', with a total of 25 items. These items consist of five subscales: conduct problems (5 items), hyperactivity (5 items), emotional problems (5 items), peer problems (5 items), and prosocial behavior (5 items), each yielding scores between 0 and 10. The Total Difficulties Score ranging from 0 to 40 was derived from the sum of the four subscale scores, excluding prosocial behavior [19]. Banding of raw scores obtained with the five SDQ subscales and the Total Difficulties Score, the scale properties were assessed as 'Low Need', 'Some Need', or 'High Need', applying recommended banding of raw scores by Matsuishi T et al. [20] both in ≤13 years and in > 13 years old.
In addition, the average sleep time duration in the last 4 weeks, which was reported by patients or caregivers and not actigraphy-measured data, was recorded at week 24, week 52, and/or end of study. Recommended sleep duration by age group was predefined using modified method reported by Hirshkowitz M et al. [21], and the shift in sleep duration from baseline to end-point (last observation carried forward; LOCF) was calculated.

Statistical analysis
Results were summarized using descriptive statistics. Continuous variables were described as mean ± standard deviation (SD). The LOCF method was used with imputation of the latest observed values. An applicable paired t-test or Wilcoxon signed-rank sum test was applied to compare the pre-dose and post-dose effect. The level of statistical significance was set at two-sided 5% and the confidence interval at two-sided 95%.
The treatment continuation rate was analyzed by Kaplan-Meier method, with the reason for discontinuation of aripiprazole censored as "transfer,", "lost to follow-up," or "improved symptoms".
The Japanese version of the ICH Medical Dictionary for Regulatory Activities (MedDRA/J version 22.1) was used in coding and classifying adverse events. Adverse events for which a causal relationship to aripiprazole could not be ruled out were considered as ADRs. All statistical analyses were performed using SAS software (version 9.3; SAS Institute Inc.).

Patient disposition
Five hundred and twenty-eight patients were enrolled at 100 sites across Japan, and 526 case reports were collected during the period of April 2017 to September 2019. The safety analysis population consisted of 510 patients. Among excluded patients, 15 patients were lost to follow-up, and one patient was not treated with aripiprazole. After excluding 21 patients with the protocol deviations (including all effectiveness measures were not assessed after treatment: n = 11, all effectiveness measures were assessed over 7 days after last dose: n = 7, the daily dose was > 15 mg: n = 2, all effectiveness were assessed after day 393: n = 1), the effectiveness analysis population consisted of 489 patients (Fig. 1).

Patient demographics
Baseline patient characteristics are summarized in Table 1. Among 510 patients included in the safety analysis, the mean age of the patient population at baseline was 10.4 ± 3.1 years, and the majority of the patients were males (73.7%) and aged 6 years or older but younger than 13 years (71.8%).

Aripiprazole dosing
The mean duration of aripiprazole treatment was 290.6 ± 151.5 days and the mean daily dose was 2.20 ± 1.85 mg.
A total of 201 patients (39.4% of the safety population) discontinued aripiprazole treatment during the surveillance period. Of the 201 patients who discontinued treatment, the most common reason for discontinuation (multiple responses were allowed) was 'request for discontinuation from the patient or family' in 33.8% (n = 68) ( Table 2) and the mean duration of treatment prior to discontinuation was 133.6 ± 113.4 days.
The continuation rate of aripiprazole treatment was 84.6% at day 168 (week 24) and 78.1% at day 364 (week 52) from the first dose (see Additional file 1).
The most common ADRs (≥0.5%) associated with extrapyramidal symptoms were tic disorders and akathisia (0.8% each), both of which were non-serious.
The mean percentile of weight was 48.36% ± 31.86% at baseline, 52.35% ± 32.86% at end-point (LOCF), and the mean change from baseline to end-point was 3.99% ± 11.65%. Percentile body weight categorical shift data are presented in Table 4. All patients with a weight in the > 90th percentile at end-point (LOCF) were in the > 75th percentile at baseline, and all patients with a weight in the ≤10th percentile at end-point (LOCF) were in the ≤25th percentile at baseline. There were no patients in which the percentiles of weight differed greatly between before and after aripiprazole treatment.
The mean baseline SDQ Total Difficulties Score was 21.1 ± 5.5 (n = 309); mean changes from baseline were − 3.3 ± 4.9 (n = 215) at week 24, − 4.3 ± 6.1 (n = 200) at week 52, and − 3.8 ± 5.6 (n = 309) at end-point (LOCF) (p < 0.0001) (Fig. 5). The mean SDQ prosocial behavior subscale score was 3.5 ± 2.5 (n = 316) at baseline, and mean changes from baseline were 0.6 ± 1.7 (n = 217) at week 24, 0.8 ± 2.1 (n = 200) at week 52, and 0.7 ± 2.0  a: Multiple responses were allowed in a patient b: Drugs using in ≥2% of Patiants (n = 316) at end-point (p < 0.0001) (Fig. 5). All SDQ subscale scores and Total Difficulties Score were significantly decreased at all assessment points compared with baseline. The shift in SDQ scale properties from baseline to end-point (LOCF) is shown in Table 5. For conduct problems, the percentage of patients changing from 'High Need' to 'Some Need' or 'Low need' was 38.8% (n = 83/214) and the percentage of patients changing from 'Some Need' to 'Low need' was 51.1% (n = 24/47). In contrast, the percentage of patients changing from 'Low Need' to 'Some Need' or 'High need' was 23.1% (n = 12/52) and the patients changing from 'Some Need' to 'High need' was 19.1% (n = 9/47). Also, similar trends were shown in hyperactivity/inattention, emotional symptoms, and prosocial behavior subscales. The shift in mean sleep time duration from baseline to end-point (LOCF) is shown in Fig. 6. The percentage of patients changing from 'Too short' to 'May be appropriate' or 'Recommended' was 55.6% (n = 15/27). In contrast, the percentage of patients changing from 'Recommended' or 'May be appropriate' to 'Too short' was 1.6% (n = 4/258). Only one patient changed from 'Too long' to 'Recommended'. No patients had a mean sleep time duration of 'May be appropriate (longer)' or 'Too long' at end-point (LOCF).

Discussion
Atypical antipsychotics are used to treat irritability, one of the behavioral symptoms associated with ASD in pediatric patients, yet there is a need for additional realworld data on the long-term safety and effectiveness of specific agents. In this surveillance, the safety and effectiveness of aripiprazole in patients (≥6 years to < 18 years old) newly treated with aripiprazole for irritability associated with ASD in children and adolescents were examined in a 52-week observation in daily clinical practice after marketing in Japan.
In the 510 patients included in the safety analysis, the treatment continuation rate was 78.1% at week 52, and the most common reason for discontinuation was 'request for discontinuation from patient or family' (33.8%). Treatment continuation might be decided by consultation between the physician and the patient or family members depending on the patient's conditions or school environment.
The mean daily dose for the entire treatment period in this surveillance was 2.20 ± 1.85 mg, and the mean daily dose of the long-term clinical study was 7.2 ± 4.0 mg [11]. The surveillance cannot be compared with the   clinical study because of differences in inclusion/exclusion criteria of patients and dose-escalation/reduction methods. In particular, baseline severity between the short-term clinical study and this surveillance was different; CGI-S scores were 4.9 ± 0.1 (mean ± standard error; SE) and 4.3 ± 0.8, and ABC-J irritability subscale scores were 26.9 ± 1.0 (mean ± SE) and 19.7 ± 9.6, respectively [9], aligning with our findings that aripiprazole was administered to patients with milder symptoms in routine practice than in the clinical study.
In 510 patients included in the safety analysis, ADRs occurred in 22.7% (n = 116/510) and the events that occurred in ≥1% of patients were somnolence (9.4%), weight increased (3.3%), nausea (1.4%), increased appetite and headache (1.2% each), and obesity (1.0%). Among these, headache and nausea were observed more frequently in the early phase of treatment, and there was no tendency for increased incidence with long-term treatment. Somnolence was observed through the surveillance period, and there were no reports of fall or traumatic injury related to somnolence. However, since the event is considered to affect school-aged pediatric patients' academic performance, monitoring of the events is needed.
In contrast, the incidence of treatment-emergent adverse events (TEAEs) was 97.7% (n = 84/86) in the Japanese clinical study, and the major events were somnolence (32.6%), influenza (29.1%) and weight increased (24.2%) [11]. Also, the major TEAEs were weight increased (23.0%) and vomiting (18.8%) in American 52week clinical study [15]. Although the backgrounds of patients, the frequency of observations, and the dose dif-   fered from those in the clinical study, somnolence and weight increased were also the most common events in the real-world treatment. For the effect on weight and growth, 0.6% of weight increase-related ADRs (weight increased and obesity) led to treatment discontinuation, and this was considered not to have a major effect on long-term treatment continuation. The mean change in body weight from baseline increased over time throughout the treatment period, but there were no major changes in weight percentile category from baseline, suggesting that weight increase is due to natural growth and not a crucial safety issue. The percentile and z-score of height and body mass index (BMI) are also suggesting that (see Additional file 4).
ABC-J irritability subscale score was 19.8 ± 9.5 (n = 396) at baseline, and the mean changes from baseline were − 5.7 ± 6.8 at week 4 and − 6.8 ± 8.3 at end-point, which were significantly decreased (p < 0.0001). The corresponding score was 26.9 ± 1.0 (mean ± SE) at the baseline of the short-term clinical study and 17.6 ± 10.0 at the baseline of the long-term clinical study in Japan. The mean changes from baseline were − 11.4 ± 1.3 (mean ± SE) at week 8 in the short-term clinical study, and − 3.2 ± 8.1 at end-point in the long-term clinical study in Japan [9][10][11]. Also, the mean change from baseline was − 6.5 ± 11.1 at end-point in American 52-week clinical study [16]. In these clinical studies, enrolled patients with ABC-J irritability subscale score of 18 or higher cannot be directly compared with the surveillance because of differences in patients and treatment characteristics. However, ABC-J irritability subscale score showed that aripiprazole improved the symptoms even in patients with relatively mild symptoms who were treated in post-marketing setting.
Interestingly, although patients with comorbid ADHD were excluded in the clinical trials under diagnosis based on DSM-IV-TR, 53.1% of patients in this surveillance had comorbidities of ADHD that did not affect the ABC-J irritability subscale score at end-point (LOCF).
In addition, overall aberrant behaviors including hyperactivity, stereotypy, inappropriate speech, and lethargy/social withdrawal were improved concurrently with irritability.
SDQ for children has not been assessed in the clinical trials [11], while total 25 items in SDQ are recorded by caregivers in this surveillance. ASD diagnosis has  been associated with the low scores on the prosocial subscale in UK cohorts [22], and social impairments are core deficits [23]. Our findings suggest that prosocial behavior, which refers to positive interactions with other people, including helping, sharing, cooperating, and comforting, may also be improved in school based settings from a social perspective as well as irritability symptoms.
Sleep duration has not been measured in prior clinical trials, whereas adequate sleep duration may not be maintained sufficiently due to irritability in the patients with ASD. The average sleep time duration in the last 4 weeks was reported by patients or caregivers and assessed in consideration of the recommended sleep time for each age [21] in this surveillance. Although concomitant use of hypnotics was not taken into account, the improvement of irritability might lead to proper sleep duration as shown in Fig. 6. The results and interpretation of sleep time duration have certain limitations as there are no actigraphy-measured data.
To our knowledge, this is the first study assessing the tolerability and effectiveness of aripiprazole in pediatric patients with ASD associated irritability over the long term, collecting a large amount of data and under actual clinical practice settings, not only for ABC-J or CGI scale but also SDQ scale, even though there are reports of clinical trials including systematic review and metaanalysis [24][25][26][27][28]. The goals of treatment are mainly to maximize an individual's functional independence and quality of life through development and learning, improvements in social skills and communication, reductions in disability and comorbidity, and promotion of independence [29]. The results of ABC-J and SDQ assessments suggested that aripiprazole improved the symptoms of irritability associated with ASD, which may have a secondarily effect in addressing these treatment goals.
The results and interpretation of safety and effectiveness have certain limitations. This surveillance was a prospective study in which the evaluation methods and measurement scales were determined in advance, and it was an observational study in daily clinical practice without a comparison group. In addition, there were variations in the reporting and evaluation and deficiencies in the assessments based on the reports made by the physicians and caregivers.